Acta Med Scand 204: 471476, 1978
Interferon Therapy in Neoplastic Disease A Preliminary R e p o r t Ivan S t r ~ y e Christophersen, r Robert Jordal, Kurt Osther, John Lindenberg, Poul Hjortkjaer Pedersen and Kurt Berg From the Department of Oncology and Radiotherapy and the Department of Gynecology and Obstetrics, Herlev University Hospital, Herlev, the Department of Clinical Chemistry, Gentofie University Hospital, Gentofte, the Department of Surgery, Frederiksberg Hospital, Copenhagen and the Institute of Microbiology, Arhus University, Arhus, Denmark
ABSTRACT. The treatment of 10 patients having neoplastic disease with exogenous i.m. interferon therapy is described. The interferon given is partially purified interferon produced from human leukocytes. Sendai virus is used as interferon inductor. The patients reported in this paper have been on treatment for periods of 2-28 months. Apart from initial periods of fever, no side-effects have been recorded. Patients suffering from bladder papillomas have shown partial regression after a few months of therapy. The other cases treated are too few to warrant any conclusions, but the therapy does seem to have been beneficial.
Due to the limited availability of interferon, only neoplastic diseases with extremely bad prognosis, such as osteosarcoma (12), one case of Hodgkin's disease (2), a few cases of myelomas and papillomas in larynx (juvenile type) (personal communication), have been reported. Until now, interferon therapy given for long periods has not shown serious sideeffects ( 1 , 3, 14, IS). Although we have not treated a great many cases to date, we have found it imperative to report our experiences from interferon therapy.
Key words: Interferon, neoplasia, treatment, papilloma of
MATERIAL AND METHODS
bladder. Acta Med Sand 204: 471, 1978. In 1957 Isaacs and Lindenmann (8) found interferon to be a substance with antiviral effect. They showed that cells infected by virus produced a protein which protects uninfected cells against virus attack. This protein was called interferon. Recent studies have demonstrated that interferon possesses immune regulatory properties ( 5 ) . Other works have demonstrated interferon-induced inhibition of cell growth in in vitro investigations (16). The cell growth inhibiting property of interferon has also been demonstrated in vivo by treating mice suffering from leukemia or malignant lymphomas, with resulting remission (4, 6). Several works from Sweden and Finland have shown that high doses of interferon administered for long periods to patients with malignant diseases are effective, and no serious side-effects have been recorded (2, 11, 12, 13, 14, 15, 17).
Interferon
The interferon was prepared from human leukocytes as described by Mogensen and Cantell (9) and subjected to partial purification by the selective precipitation of contaminating proteins from a 94 % ethanolic solution (9). The preparations used for therapy contained about 4 mill. interferon units (IFU) per ml and had a protein content of approximately 0.5 mg/l mill. IFU, corresponding to 1-2x 10" IFU/mg protein. Interferon treatment
Interferon was administered as a partially purified interferon (P-IF) i.m. as described by Strander et al. (13, 14). The doses employed are stated in Results. Testing of the interferon preparations
The interferon preparations were tested for activity on U-cells using plaque technique (14). The protein bands were checked on SDS PAGE and compared to P-IFpreparations, provided by Dr K. Cantell. Cell inhibition effect was tested on Daudi cells (7). The preparations were checked for sterility and pyrogenicity. Abbreviations: IFU=interferon unit, P-IF=purified in-
terferon. Actu
Med Scund 2iM
412
I . Sir%yer Christophersen e t ul.
CASE REPORTS Patient I A 16-year-old girl with osteosarcoma positioned in the distal part of left femur. She was treated initially 1.2 years ago with amputation of left femur. The patient had no clinical signs of metastases. Interferon treatment was commenced with P-IF, 4 mill. IFU i.m. daily for one month starting immediately prior to operation, followed by P-IF injections 3 times a week, to be continued for a total of 1.5 years. Cytostutic regimen Four weeks after surgery the patient was treated for 6 weeks with high-dose methotrexate, 3 OOO 'mg per course followed by citrovorum rescue factor. Purienr 2 A 29-year-old man with an osteosarcoma in the proximal part of humerus. He was subjected to an amputation of the right humeroscapular joint 3.6 years ago. Left lung metastases were detected 6 months after the operation, and thoracotomy with extirpation of metastatic tissue was performed. Pulmonal metastases were found after this operation. P-IF treatment with 2 mill. IFU i.m. was started 3 years ago, three times a week, followed 1 year ago by 4 mill. IFU daily for one month, since then 3 doses a week. Treatment is continuing. Cyiosiutic regimen Combined cytostatic courses consisting of high-dose methotrexate, Adriamycin and vincristine were started 3.1 years ago. Patient 3 An 8-year-old boy with an Ewing sarcoma localized to the right tibia (proximal part). Initial treatment was highvoltage irradiation (2.36 Gy/20F, 4F/w, 82 TDF, CRE I555 reu.). The patient was given interferon, 4 mill. IFU, immediately after irradiation, daily doses for 14 days, and thereafter 3 weekly doses. Until now, the patient has been on treatment with interferon for 1 year, and is to continue treatment for 1.5 years. Cyiosiaiic regimen Combined cytostatic treatment was started at the time of irradiation. The treatment consisted of dactinomycin, Oncovin, cyclophosphamide and Adriamycin; 4 courses were given at intervals of 2 months. Paiieni 4 A 61-year-old woman suffering from a synovial sarcoma. She was treated with amputation of distal part of left femur. Immediately after surgery, the patient was given interferon, 4 mill. IFU daily for one month, followed by 4 mill. IFU 3 times a week. She has been on treatment for half a year and is to continue for 1.5 years. Cyiosiuiic regimen None. Actii
Mrd Sccmd 204
Puiieni 5 A 34-year-old woman suffering from an osteosarcoma positioned in the middle of the left humerus. She was subjected to amputation of left humeroscapular joint 12 months ago. No metastases were recorded. Starting 3 months ago, the patient was given interferon, 4 mill. IFU daily, for one month and 3 times a week during the following two months. Cytosiatic regimen Adriamycin, 60 mg/m2every three weeks until a total dose of 450 mg/m2, had been given before admission to our department. Putient 6 A 47-year-old woman suffering from malignant mesenchymoma in the middle part of left femur. Three months ago, the patient was subjected to local resection. She received postoperative high-voltage irradiation (3.0 Gy/l5 F, 4 F/w, 76 TDF, CRE 1590 reu.). Starting 2 months ago, interferon is being administered, 4 mill. IFU daily, for one month and thereafter 3 times weekly. Cytosiaiic regimen Fourteen days after surgery the patient was given Adriamycin, 60 mg/m2 every 4 weeks. Scheduled total dose is 450 mg/m2. Cyclophosphamide. I50 mg daily for 7 days every 4 weeks. Puiieni 7 A 66-year-old woman had been subjected to explorative pyelotomy 6 years ago because of papillomas in renal pelvis (grade 11). Nephroureterectomy (left side) was performed 3 years ago because of complete papillomatous degeneration in renal pelvis. Until 1 year ago, the patient was treated several times with electrocoagulation because of recidivating multiple papillomas in the bladder. One year ago, interferon treatment was started with 4 mill. IFU daily for 2 months, followed by 4 mill. IFU 3 times a week. The treatment is to be continued for a total of 1.5 years. Cyiosiutic regimen None. Paiieni 8 A 54-year-old man, in whom treatment with electrocoagulation was initiated 4 years ago because of papillomas in the bladder (grade I). Until half a year ago, the patient was electrocoagulated several times for multiple papillomas. Interferon treatment was started half a year ago at the same doses as given to patient 7. Cytosiatic regimen None. Patient 9 A 46-year-old woman who has been suffering for 7 years from widespread papillomas (grade 11) in the bladder and been electrocoagulated several times. Interferon treatment was started with 4 mill. IFU daily for one month and
Interferon therapy in neoplastic disease
Table 1. Results of interferon therapy in patients 1 4 with bone sarcomas and patient 10 with cancer uteri Pat
2
0 I
,
l
4 ,
l
6 l
l
8 ,
l
12
10 ,
l
,
l
,
1 C . IF i
?
i
a
16
1L l
l
l
r
3
4
9
O
1
1
1
22 1
21 1
1
45
-
29
8
20
18 l
I C , IF 8
2
C
Months
Age ly.)
Sax
no.
473
m
c
C. IF, I r r .
J
S.C. IF
+?
I
/
I
9
6
1
0
s
S,C, IF
I
5
0
34
6
9
4
7
10
?
34
1-B
’
J
S.C, IF,Irr
0
IF, lrr.
O=Periods without metastases, .=periods with metastases, *?=no clinical signs of metastases, S=surgery, C= cytostatic treatment started, IF=interferon treatment started, Irr.= high-voltage irradiation. 3 times a week during the fallowing months. The patient has been on interferon treatment for 7 months. Cytostatic regimen
None. Patient I0
A 34-year-old woman with a cancer colli uteri stadium I1 B. The patient was given high-voltage irradiation on gynecological areas (39,50 Oy/lO F, 2 F/w, TDF 82, CRE 1560 reu.). Local cobolt irradiation using afterloading principle. At the time of irradiation, interferon treatment was started with 4 mill. IFU daily for one month, followed by 3 times a week, and the patient has now been on interferon treatment for 8 months. Cyrostatic regimen
None.
RESULTS The number of patients treated is too small and the observation periods during treatment are too short for definite conclusions about the effect of interferon on cancer. But the following results can be
stated: Patients 3-6 have not developed any metastases to date (Table I). Patient I developed lung metastases 8 months after the start of interferon treatment. Thoracotomy was performed but was not radical. After a short pause she has continued with interferon treatment. Furthermore, high-dose methotrexate is scheduled. Treatment of patient 2 with interferon and cytostatics was started during his first metastatic period (Table I) and he was brought into remission for a period of 17 months. Relapse reappeared in the lungs, and (radical) thoracotomy was performed. Still under interferon treatment, the patient obtained remission for a further 12 months. He then developed a solitary metastasis in thoracal vertebra VIII, and paresis of both legs. Laminectomy for decompression was performed. After a short pause, the interferon treatment was continued. The paresis disappeared shortly after operation and the patient has now had a period of 7 months without any progression in his disease. After treatment for a few months with interferon, Arra Med Scund 21)Q
~
474
I . Strrayer Christophersen et d.
patients 7, 8 and 9 showed normalization of their bladder urothelium. Regression of papillomas smaller than l cm was detected whereas those larger than I cm were stationary. Patient 10 (Table I), who had a stage 2 B collum cancer before irradiation and interferon treatment, has been without local recurrence or detectable metastases for 8 months. DISCUSSION In recent years, interest in the clinical use of interferon has grown considerably. Relatively few cases have been published, which reflects the limited availability of interferon. Our experience with interferon, based on the 10 patients described, is that it may be utilized for long-term treatment without any other serious side-effects than fever during the initiation of treatment. No allergic manifestations have been observed. We have no explanation for the initial fever, though it may be directly associated with the working mechanism of interferon (10). Hospitalization is needed only at the initiation of treatment with interferon, which may otherwise be administered at home. The size of the dose is approximately that used by Strander et al., 4 x lo6 IFU (personal communication). Only further clinical investigations can reveal any benefit of higher doses. The reasons why we have given interferon therapy to patients with bone sarcomas are that Strander et al. have found this therapy to be effective on osteosarcoma (14) and that the growth of osteosarcoma cells in tissue culture seems to be inhibited by interferon doses corresponding to the concentrations in the patients (16). Strander et al. found that 64 % of patients treated with interferon show no metastases after 21 years, compared with 32 % of the control group, and that 73 % of patients were still alive after 21 years of interferon treatment, compared with 35% of the control group (14). Based on these facts, we consider that interferon treatment should always be used in the primary treatment of patients with osteosarcomas, and that the treatment should be initiated shortly after establishing the diagnosis. In our patient 2 with osteosarcoma and lung metastases we started treatment with interferon under this condition. During combined treatment with cytostatics and interferon we succeeded in bringing the patient into remission for a period of 17 months. This long period of remission is noteworthy compared to Artii Med Scund204
the general fate of patients suffering from osteosarcomas with lung metastases (14). The next metastasis, situated in VIII vertebra as a sole tumour, appeared after an interval of 12 months. It was treated as described, and interferon treatment was started again with daily doses of 4 mill. IFU. Furthermore, it is of interest that 7 months after the last surgery, the patient shows no sign of progression in his disease. Thus it may be possible to begin interferon treatment with some benefit for the patient even though lung metastases have developed. The patient group referred to (14) has only received interferon therapy. For 5 out of 6 patients with bone sarcomas we have chosen to combine the interferon treatment with cytostatics. The reason why we have given interferon to three patients with bladder papillomas and to one patient with cancer colli uteri is that virus might be a causal agent for these types of neoplasms. In all three patients regression was found in the small papillomas, but not in the large. Interestingly enough, we have not seen any exacerbation of the papillomas. Interferon may be useful, for example, in the therapy of patients suffering from bladder papillomas. One patient suffering from cancer colli uteri received interferon as an adjuvant therapy. Further randomized investigations with interferon in this disease are required. The effect of interferon treatment on cancer will be investigated in larger scale, systematic studies.
REFERENCES I . Ahlstrijm, L . , Dohlwitz. A., Strander, H . , Carlstrom, G. & Cantell, K.: Interferon in acute leukaemia in children. Lancet I : 166, 1974. 2. Blomberg, H., Cantell, K.., Johansson, B., Lagergren, C., Ringborg, U.& Strander, H.: Interferon therapy in Hodgkin's disease. A case report. Acta Med Scand 199: 527. 1976. 3. Cantell, K., Hirvonen, S., Mogensen, K . E. & Pyhalii, L.: Human leucocyte interferon: production, purification, stability and animal experiments. In: The production and use of interferon for the treatment and prevention of human virus infections (ed. C. Waymouth), p. 35. Proceedings of a Tissue Culture Association Workshop held at Lake Placid, 1973. (In vitro monograph, 3.) Tissue Culture Association, Rockville Md., USA 1974. 4. Chirigos, M. A. & Pearson, J. W.: Cure of rnurine leukemia with drug and interferon treatment. J Natl Cancer Inst 51: 1367, 1973. 5. Degr6, M. & Elgjo, K.: Influence of synthetic polynucleotides and interferon on in vitro growth of
Interferon therapy in neoplastic disease
6. 7.
8. 9.
10.
1I.
cells derived from a mouse sarcoma. Acta Pathol Microbiol Scand (A) (Suppl) 248: 61, 1974. Gresser, I.: Antitumour effects of interferon. Adv Cancer Res 16: 97. 1972. Hilfenhaus, J., Damm, H., Karges, H. E. & Manthey, K. F.: Growth inhibition of human lymphoblastoid Daudi cells in vitro by interferon preparations. Arch Virol 51: 87, 1976. Isaacs, A. & Lindemann, J.: Virus interference. I. The interferon. Proc Roy Soc B 147: 258, 1957. Mogensen, K. E. & Cantell, K.: Production and preparation of human leukocyte interferon. Pharmacol Ther C, vol. I: 369, 1977. Scott, G. M., Butler, J. K., Cartwright, T., Richards, B. M., Kingham, J. G., Wright, R. & Tyrrell, D.: Interferon skin reactivity and pyrexial reactions. Lancet 2~402,1977. Strander, H. & Cantell, K.: Studies on antiviral and antitumor effects of human leukocyte interferon in vitro and in vivo. In: The production and use of interferon for the treatment and prevention of human virus infections (ed. C. Waymouth) p. 49. Proceedings of a Tissue Culture Association Workshop held at Lake Placid, 1973 (in vitro monograph, 3). Tissue Culture Association, Rockville Md., USA 1974.
475
12. Strander, H., Cantell, K., Carlstrom, G., Ingimarsson, S., Jakobsson, P. A. & Nilsonne, U.: Acute
infections in interferon-treated patients with osteosarcoma: preliminary report of a comparative study. J Infect Dis (Suppl A) 133: 245, 1976. 13. Strander, H., Cantell, K., Carlstrom, G. & Jakobsson, P. A.: Systemic administration of potent interferon to man. J Natl Cancer Inst 51: 733, 1973. 14. Strander, H., Cantell, K., Ingimarsson, S., Jakobsson, P. A., Nilsonne, U.& Soderberg, G.: Interferon treatment of osteogenic sarcoma: A clinical trial. Fogarty International Center Proceedings no. 28. US Government Printing Office, Washington D. C. 28: 377, 1977. 15. Strander, H., Cantell, K., Jakobsson, P.
A., Nilsonne, U. & Saderberg, G.: Exogenous interferon therapy of osteogenic sarcoma. Acta Orthop Scand
45: 958, 1974. 16. Strander, H. & Einhorn, S.: Effect of human leuko-
cyte interferon on the growth of human osteosarcoma cells in tissue culture. Int J Cancer 19: 468, 1977. 17. Strander, H., Jakobsson, P. A., Carlstrom, G. & Cantell, K.: Administration of potent interferon to patients with malignant diseases. Cancer Cytol 13: 18, 1974.
Aclu Med Srund 204
Interferon Therapy in Neoplastic Disease A Preliminary R e p o r t Ivan S t r ~ y e Christophersen, r Robert Jordal, Kurt Osther, John Lindenberg, Poul Hjortkjaer Pedersen and Kurt Berg From the Department of Oncology and Radiotherapy and the Department of Gynecology and Obstetrics, Herlev University Hospital, Herlev, the Department of Clinical Chemistry, Gentofie University Hospital, Gentofte, the Department of Surgery, Frederiksberg Hospital, Copenhagen and the Institute of Microbiology, Arhus University, Arhus, Denmark
ABSTRACT. The treatment of 10 patients having neoplastic disease with exogenous i.m. interferon therapy is described. The interferon given is partially purified interferon produced from human leukocytes. Sendai virus is used as interferon inductor. The patients reported in this paper have been on treatment for periods of 2-28 months. Apart from initial periods of fever, no side-effects have been recorded. Patients suffering from bladder papillomas have shown partial regression after a few months of therapy. The other cases treated are too few to warrant any conclusions, but the therapy does seem to have been beneficial.
Due to the limited availability of interferon, only neoplastic diseases with extremely bad prognosis, such as osteosarcoma (12), one case of Hodgkin's disease (2), a few cases of myelomas and papillomas in larynx (juvenile type) (personal communication), have been reported. Until now, interferon therapy given for long periods has not shown serious sideeffects ( 1 , 3, 14, IS). Although we have not treated a great many cases to date, we have found it imperative to report our experiences from interferon therapy.
Key words: Interferon, neoplasia, treatment, papilloma of
MATERIAL AND METHODS
bladder. Acta Med Sand 204: 471, 1978. In 1957 Isaacs and Lindenmann (8) found interferon to be a substance with antiviral effect. They showed that cells infected by virus produced a protein which protects uninfected cells against virus attack. This protein was called interferon. Recent studies have demonstrated that interferon possesses immune regulatory properties ( 5 ) . Other works have demonstrated interferon-induced inhibition of cell growth in in vitro investigations (16). The cell growth inhibiting property of interferon has also been demonstrated in vivo by treating mice suffering from leukemia or malignant lymphomas, with resulting remission (4, 6). Several works from Sweden and Finland have shown that high doses of interferon administered for long periods to patients with malignant diseases are effective, and no serious side-effects have been recorded (2, 11, 12, 13, 14, 15, 17).
Interferon
The interferon was prepared from human leukocytes as described by Mogensen and Cantell (9) and subjected to partial purification by the selective precipitation of contaminating proteins from a 94 % ethanolic solution (9). The preparations used for therapy contained about 4 mill. interferon units (IFU) per ml and had a protein content of approximately 0.5 mg/l mill. IFU, corresponding to 1-2x 10" IFU/mg protein. Interferon treatment
Interferon was administered as a partially purified interferon (P-IF) i.m. as described by Strander et al. (13, 14). The doses employed are stated in Results. Testing of the interferon preparations
The interferon preparations were tested for activity on U-cells using plaque technique (14). The protein bands were checked on SDS PAGE and compared to P-IFpreparations, provided by Dr K. Cantell. Cell inhibition effect was tested on Daudi cells (7). The preparations were checked for sterility and pyrogenicity. Abbreviations: IFU=interferon unit, P-IF=purified in-
terferon. Actu
Med Scund 2iM
412
I . Sir%yer Christophersen e t ul.
CASE REPORTS Patient I A 16-year-old girl with osteosarcoma positioned in the distal part of left femur. She was treated initially 1.2 years ago with amputation of left femur. The patient had no clinical signs of metastases. Interferon treatment was commenced with P-IF, 4 mill. IFU i.m. daily for one month starting immediately prior to operation, followed by P-IF injections 3 times a week, to be continued for a total of 1.5 years. Cytostutic regimen Four weeks after surgery the patient was treated for 6 weeks with high-dose methotrexate, 3 OOO 'mg per course followed by citrovorum rescue factor. Purienr 2 A 29-year-old man with an osteosarcoma in the proximal part of humerus. He was subjected to an amputation of the right humeroscapular joint 3.6 years ago. Left lung metastases were detected 6 months after the operation, and thoracotomy with extirpation of metastatic tissue was performed. Pulmonal metastases were found after this operation. P-IF treatment with 2 mill. IFU i.m. was started 3 years ago, three times a week, followed 1 year ago by 4 mill. IFU daily for one month, since then 3 doses a week. Treatment is continuing. Cyiosiutic regimen Combined cytostatic courses consisting of high-dose methotrexate, Adriamycin and vincristine were started 3.1 years ago. Patient 3 An 8-year-old boy with an Ewing sarcoma localized to the right tibia (proximal part). Initial treatment was highvoltage irradiation (2.36 Gy/20F, 4F/w, 82 TDF, CRE I555 reu.). The patient was given interferon, 4 mill. IFU, immediately after irradiation, daily doses for 14 days, and thereafter 3 weekly doses. Until now, the patient has been on treatment with interferon for 1 year, and is to continue treatment for 1.5 years. Cyiosiaiic regimen Combined cytostatic treatment was started at the time of irradiation. The treatment consisted of dactinomycin, Oncovin, cyclophosphamide and Adriamycin; 4 courses were given at intervals of 2 months. Paiieni 4 A 61-year-old woman suffering from a synovial sarcoma. She was treated with amputation of distal part of left femur. Immediately after surgery, the patient was given interferon, 4 mill. IFU daily for one month, followed by 4 mill. IFU 3 times a week. She has been on treatment for half a year and is to continue for 1.5 years. Cyiosiuiic regimen None. Actii
Mrd Sccmd 204
Puiieni 5 A 34-year-old woman suffering from an osteosarcoma positioned in the middle of the left humerus. She was subjected to amputation of left humeroscapular joint 12 months ago. No metastases were recorded. Starting 3 months ago, the patient was given interferon, 4 mill. IFU daily, for one month and 3 times a week during the following two months. Cytosiatic regimen Adriamycin, 60 mg/m2every three weeks until a total dose of 450 mg/m2, had been given before admission to our department. Putient 6 A 47-year-old woman suffering from malignant mesenchymoma in the middle part of left femur. Three months ago, the patient was subjected to local resection. She received postoperative high-voltage irradiation (3.0 Gy/l5 F, 4 F/w, 76 TDF, CRE 1590 reu.). Starting 2 months ago, interferon is being administered, 4 mill. IFU daily, for one month and thereafter 3 times weekly. Cytosiaiic regimen Fourteen days after surgery the patient was given Adriamycin, 60 mg/m2 every 4 weeks. Scheduled total dose is 450 mg/m2. Cyclophosphamide. I50 mg daily for 7 days every 4 weeks. Puiieni 7 A 66-year-old woman had been subjected to explorative pyelotomy 6 years ago because of papillomas in renal pelvis (grade 11). Nephroureterectomy (left side) was performed 3 years ago because of complete papillomatous degeneration in renal pelvis. Until 1 year ago, the patient was treated several times with electrocoagulation because of recidivating multiple papillomas in the bladder. One year ago, interferon treatment was started with 4 mill. IFU daily for 2 months, followed by 4 mill. IFU 3 times a week. The treatment is to be continued for a total of 1.5 years. Cyiosiutic regimen None. Paiieni 8 A 54-year-old man, in whom treatment with electrocoagulation was initiated 4 years ago because of papillomas in the bladder (grade I). Until half a year ago, the patient was electrocoagulated several times for multiple papillomas. Interferon treatment was started half a year ago at the same doses as given to patient 7. Cytosiatic regimen None. Patient 9 A 46-year-old woman who has been suffering for 7 years from widespread papillomas (grade 11) in the bladder and been electrocoagulated several times. Interferon treatment was started with 4 mill. IFU daily for one month and
Interferon therapy in neoplastic disease
Table 1. Results of interferon therapy in patients 1 4 with bone sarcomas and patient 10 with cancer uteri Pat
2
0 I
,
l
4 ,
l
6 l
l
8 ,
l
12
10 ,
l
,
l
,
1 C . IF i
?
i
a
16
1L l
l
l
r
3
4
9
O
1
1
1
22 1
21 1
1
45
-
29
8
20
18 l
I C , IF 8
2
C
Months
Age ly.)
Sax
no.
473
m
c
C. IF, I r r .
J
S.C. IF
+?
I
/
I
9
6
1
0
s
S,C, IF
I
5
0
34
6
9
4
7
10
?
34
1-B
’
J
S.C, IF,Irr
0
IF, lrr.
O=Periods without metastases, .=periods with metastases, *?=no clinical signs of metastases, S=surgery, C= cytostatic treatment started, IF=interferon treatment started, Irr.= high-voltage irradiation. 3 times a week during the fallowing months. The patient has been on interferon treatment for 7 months. Cytostatic regimen
None. Patient I0
A 34-year-old woman with a cancer colli uteri stadium I1 B. The patient was given high-voltage irradiation on gynecological areas (39,50 Oy/lO F, 2 F/w, TDF 82, CRE 1560 reu.). Local cobolt irradiation using afterloading principle. At the time of irradiation, interferon treatment was started with 4 mill. IFU daily for one month, followed by 3 times a week, and the patient has now been on interferon treatment for 8 months. Cyrostatic regimen
None.
RESULTS The number of patients treated is too small and the observation periods during treatment are too short for definite conclusions about the effect of interferon on cancer. But the following results can be
stated: Patients 3-6 have not developed any metastases to date (Table I). Patient I developed lung metastases 8 months after the start of interferon treatment. Thoracotomy was performed but was not radical. After a short pause she has continued with interferon treatment. Furthermore, high-dose methotrexate is scheduled. Treatment of patient 2 with interferon and cytostatics was started during his first metastatic period (Table I) and he was brought into remission for a period of 17 months. Relapse reappeared in the lungs, and (radical) thoracotomy was performed. Still under interferon treatment, the patient obtained remission for a further 12 months. He then developed a solitary metastasis in thoracal vertebra VIII, and paresis of both legs. Laminectomy for decompression was performed. After a short pause, the interferon treatment was continued. The paresis disappeared shortly after operation and the patient has now had a period of 7 months without any progression in his disease. After treatment for a few months with interferon, Arra Med Scund 21)Q
~
474
I . Strrayer Christophersen et d.
patients 7, 8 and 9 showed normalization of their bladder urothelium. Regression of papillomas smaller than l cm was detected whereas those larger than I cm were stationary. Patient 10 (Table I), who had a stage 2 B collum cancer before irradiation and interferon treatment, has been without local recurrence or detectable metastases for 8 months. DISCUSSION In recent years, interest in the clinical use of interferon has grown considerably. Relatively few cases have been published, which reflects the limited availability of interferon. Our experience with interferon, based on the 10 patients described, is that it may be utilized for long-term treatment without any other serious side-effects than fever during the initiation of treatment. No allergic manifestations have been observed. We have no explanation for the initial fever, though it may be directly associated with the working mechanism of interferon (10). Hospitalization is needed only at the initiation of treatment with interferon, which may otherwise be administered at home. The size of the dose is approximately that used by Strander et al., 4 x lo6 IFU (personal communication). Only further clinical investigations can reveal any benefit of higher doses. The reasons why we have given interferon therapy to patients with bone sarcomas are that Strander et al. have found this therapy to be effective on osteosarcoma (14) and that the growth of osteosarcoma cells in tissue culture seems to be inhibited by interferon doses corresponding to the concentrations in the patients (16). Strander et al. found that 64 % of patients treated with interferon show no metastases after 21 years, compared with 32 % of the control group, and that 73 % of patients were still alive after 21 years of interferon treatment, compared with 35% of the control group (14). Based on these facts, we consider that interferon treatment should always be used in the primary treatment of patients with osteosarcomas, and that the treatment should be initiated shortly after establishing the diagnosis. In our patient 2 with osteosarcoma and lung metastases we started treatment with interferon under this condition. During combined treatment with cytostatics and interferon we succeeded in bringing the patient into remission for a period of 17 months. This long period of remission is noteworthy compared to Artii Med Scund204
the general fate of patients suffering from osteosarcomas with lung metastases (14). The next metastasis, situated in VIII vertebra as a sole tumour, appeared after an interval of 12 months. It was treated as described, and interferon treatment was started again with daily doses of 4 mill. IFU. Furthermore, it is of interest that 7 months after the last surgery, the patient shows no sign of progression in his disease. Thus it may be possible to begin interferon treatment with some benefit for the patient even though lung metastases have developed. The patient group referred to (14) has only received interferon therapy. For 5 out of 6 patients with bone sarcomas we have chosen to combine the interferon treatment with cytostatics. The reason why we have given interferon to three patients with bladder papillomas and to one patient with cancer colli uteri is that virus might be a causal agent for these types of neoplasms. In all three patients regression was found in the small papillomas, but not in the large. Interestingly enough, we have not seen any exacerbation of the papillomas. Interferon may be useful, for example, in the therapy of patients suffering from bladder papillomas. One patient suffering from cancer colli uteri received interferon as an adjuvant therapy. Further randomized investigations with interferon in this disease are required. The effect of interferon treatment on cancer will be investigated in larger scale, systematic studies.
REFERENCES I . Ahlstrijm, L . , Dohlwitz. A., Strander, H . , Carlstrom, G. & Cantell, K.: Interferon in acute leukaemia in children. Lancet I : 166, 1974. 2. Blomberg, H., Cantell, K.., Johansson, B., Lagergren, C., Ringborg, U.& Strander, H.: Interferon therapy in Hodgkin's disease. A case report. Acta Med Scand 199: 527. 1976. 3. Cantell, K., Hirvonen, S., Mogensen, K . E. & Pyhalii, L.: Human leucocyte interferon: production, purification, stability and animal experiments. In: The production and use of interferon for the treatment and prevention of human virus infections (ed. C. Waymouth), p. 35. Proceedings of a Tissue Culture Association Workshop held at Lake Placid, 1973. (In vitro monograph, 3.) Tissue Culture Association, Rockville Md., USA 1974. 4. Chirigos, M. A. & Pearson, J. W.: Cure of rnurine leukemia with drug and interferon treatment. J Natl Cancer Inst 51: 1367, 1973. 5. Degr6, M. & Elgjo, K.: Influence of synthetic polynucleotides and interferon on in vitro growth of
Interferon therapy in neoplastic disease
6. 7.
8. 9.
10.
1I.
cells derived from a mouse sarcoma. Acta Pathol Microbiol Scand (A) (Suppl) 248: 61, 1974. Gresser, I.: Antitumour effects of interferon. Adv Cancer Res 16: 97. 1972. Hilfenhaus, J., Damm, H., Karges, H. E. & Manthey, K. F.: Growth inhibition of human lymphoblastoid Daudi cells in vitro by interferon preparations. Arch Virol 51: 87, 1976. Isaacs, A. & Lindemann, J.: Virus interference. I. The interferon. Proc Roy Soc B 147: 258, 1957. Mogensen, K. E. & Cantell, K.: Production and preparation of human leukocyte interferon. Pharmacol Ther C, vol. I: 369, 1977. Scott, G. M., Butler, J. K., Cartwright, T., Richards, B. M., Kingham, J. G., Wright, R. & Tyrrell, D.: Interferon skin reactivity and pyrexial reactions. Lancet 2~402,1977. Strander, H. & Cantell, K.: Studies on antiviral and antitumor effects of human leukocyte interferon in vitro and in vivo. In: The production and use of interferon for the treatment and prevention of human virus infections (ed. C. Waymouth) p. 49. Proceedings of a Tissue Culture Association Workshop held at Lake Placid, 1973 (in vitro monograph, 3). Tissue Culture Association, Rockville Md., USA 1974.
475
12. Strander, H., Cantell, K., Carlstrom, G., Ingimarsson, S., Jakobsson, P. A. & Nilsonne, U.: Acute
infections in interferon-treated patients with osteosarcoma: preliminary report of a comparative study. J Infect Dis (Suppl A) 133: 245, 1976. 13. Strander, H., Cantell, K., Carlstrom, G. & Jakobsson, P. A.: Systemic administration of potent interferon to man. J Natl Cancer Inst 51: 733, 1973. 14. Strander, H., Cantell, K., Ingimarsson, S., Jakobsson, P. A., Nilsonne, U.& Soderberg, G.: Interferon treatment of osteogenic sarcoma: A clinical trial. Fogarty International Center Proceedings no. 28. US Government Printing Office, Washington D. C. 28: 377, 1977. 15. Strander, H., Cantell, K., Jakobsson, P.
A., Nilsonne, U. & Saderberg, G.: Exogenous interferon therapy of osteogenic sarcoma. Acta Orthop Scand
45: 958, 1974. 16. Strander, H. & Einhorn, S.: Effect of human leuko-
cyte interferon on the growth of human osteosarcoma cells in tissue culture. Int J Cancer 19: 468, 1977. 17. Strander, H., Jakobsson, P. A., Carlstrom, G. & Cantell, K.: Administration of potent interferon to patients with malignant diseases. Cancer Cytol 13: 18, 1974.
Aclu Med Srund 204
